In Pursuit of Understanding the Crash - by Todd Davenport

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In Pursuit of Understanding the Crash<br>What Post-Exertional Physiology Tells Us About ME/CFS

Todd Davenport<br>Apr 16, 2026

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Myalgic encephalomyelitis is characterized by post-exertional malaise (PEM).1,2 PEM is variously defined, but it involves an abnormal multi-system and multi-symptom response to often-trivial levels of exertion. It frequently results in severe disability. Everyone’s specific pattern of signs and symptoms is different, but they all have in common a worsening after exertion. Solving PEM would solve ME/CFS.<br>The failure of medicine and science to understand ME/CFS has been a shortcoming of theory, not technology. For decades, clinicians have assumed that exertion reveals health. The idea is relatively simple, and it holds up most of the time. If you stress the system and observe the resulting performance of physiological systems under load, then you can infer capacity, and counterfactually, pathology. However, ME/CFS is an important exception to this rule.<br>Thanks for reading Todd’s Substack! Subscribe for free to receive new posts and support my work.

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Functional capacity in people with ME/CFS may be significantly compromised. But there is often a delay between the exertion and the worsening.3 Clinicians and scientists long have assumed this delay must signal a problem with motivation, beliefs, and fear. However, what ME/CFS research has surfaced slowly over time is something that medicine is still in its infancy in understanding: what happens after exertion, the biology of recovery. And the data in ME/CFS are now too coherent to dismiss.

Failure of Biological Recovery is Unusual and Unique to ME/CFS<br>The most consistent finding in ME/CFS research is also the most instructive. Patients cannot reproduce energy output on repeat exertion, whether physical, cognitive, emotional, or environmental. I’m an exercise physiologist, so I understand this literature the best and the literature is probably best developed related to physical exertion. Across multiple centers all over the world, two-day cardiopulmonary exercise testing (CPET) demonstrates that people with ME/CFS show objective declines in volume of oxygen consumed and workload at submaximal exertion on the second day, despite showing maximal effort on both days.4-6 ME/CFS is a crisis of reproducibility in science, just not the way we normally talk about it.<br>This failure of biological recovery does not occur in healthy controls, deconditioned people, or in other chronic diseases, including heart failure, chronic obstructive pulmonary disease, and multiple sclerosis.7 It is not fatigue. Rather, it is failed metabolic recovery. Attempts to dismiss this finding have relied on underpowered null studies or inappropriate analyses that erase stratified effects. (More on how ME/CFS researchers have used and abused CPET studies in future articles.) Larger and more carefully analyzed studies continue to confirm impaired reproducibility as a defining signature of PEM.4<br>If medicine and science treated exertional responses the same way it treats glucose testing, the pathophysiology of ME/CFS would have become obvious decades ago. And we would avoid the constant misapplications of the biopsychosocial approach to ‘treat’ the pathophysiology of ME/CFS that still divert precious attention, time, and resources today.

PEM is a Failure of Bioenergetic Recovery<br>Exercise physiology tells us the process of exertion is not completed at task termination. Recovery means further exertion. It requires mitochondrial substrate switching, redox normalization, autonomic rebalancing, immune system activation, and tissue repair signaling. However, this sequence breaks in ME/CFS. Multi-omics studies show that after an initial bout of exertion, ME/CFS patients exhibit continued impairment TCA cycle flux and fatty acid β-oxidation, reduced ATP generation and altered AMP/ADP ratios, persistent redox imbalance, complement activation and innate immune amplification, and lipidomic signatures consistent with inflammatory repair failure.8,9 All of these are worse after effort and correlated with symptom severity.<br>Simply put, the bodies of people with ME/CFS can not efficiently do the work of recovery. And because these abnormalities are found in people with ME/CFS but not matched deconditioned controls, we can confidently say that PEM is not deconditioning.

The Immune System Signals Persistent Danger in PEM<br>Normal exercise produces a transient inflammatory response followed by rapid resolution. However, people living with ME/CFS show the opposite pattern. A diverse body of studies demonstrate Exaggerated complement (C4a) activation post-exercise, abnormal toll‑like receptor and IL-10 gene expression, and heightened oxidative stress with delayed antioxidant responses.8,10 These immune changes align with PEM.<br>Recent large multi-omics studies have gone further,...